The invention relates generally to cancer and tumor suppressor genes.
Proliferation of normal cells is thought to be regulated by growth-promoting proto-oncogenes and by growth-constraining tumor suppressor genes (Weinberg, 1991, Science 254:1138). Genetic alterations that inactivate tumor suppressor genes or that activate proto-oncogenes free cells from growth constraints imposed by the non-altered genes, thereby enabling tumor growth. Accumulation of genetic aberrations in a cell in vivo causes the cell to proceed from a normal growth or quiescent stage, potentially through a discernable pre-neoplastic stage, to a cancerous stage in which the cell replicates abnormally quickly, and potentially spreads to body locations at which the cell is not normally found (Knudson, 1993, Proc. Natl. Acad. Sci. USA 90:10914; Nowell, 1993, Adv. Cancer Res. 62:1).
The presence of a tumor suppressor gene at a particular chromosomal location is sometimes evidenced by an increased prevalence of loss of heterozygosity (LOH) at the chromosomal location in tumor tissues, relative to non-cancerous tissue (Weinberg, 1991, Science 254:1138; Lasko et al., 1991, Ann. Rev. Genet. 25:281; Knudson, 1993, Proc. Natl. Acad. Sci. USA 90:10914; Nowell, 1993, Adv. Cancer Res. 62:1). Allelotyping studies indicate that allelic loss(es) on chromosome 8p, particularly at band 21-22, are associated with various tumors, including prostate tumors, breast tumors, head and neck squamous cell carcinomas, urinary bladder carcinomas, hepatocellular carcinomas, and hematological malignancies (Kagan et al., 1995, Oncogene 11:2121; Macoska et al., 1995, Cancer Res. 55:5390; Jenkins et al., 1998, Genes Chromosom. Cancer 21:131; Yaremko et al., 1995, Genes Chromosom. Cancer 13:186; Yaremko et al., 1996, Genes Chromosom. Cancer 16:189; Kerangueven et al., 1997, Cancer Res. 57:5469; Anbazhagan et al., 1998, Am. J. Pathol. 152:815; El-Naggar et al., 1998, Oncogene 16:2983; Sunwoo et al., 1996, Genes Chromosom. Cancer 16:164; Wu et al., 1997, Genes Chromosom. Cancer 20:347; Wagner et al., 1997, Am. J. Pathol. 151:753; Boige et al., 1997, Cancer Res. 57:1986; Takeuchi et al., 1995, Cancer Res. 55:5377).
Studies in which chromosome regions were transferred into tumor cells have provided evidence that one or more tumor suppressor genes is present at human chromosome location 8p (Gustafson et al., 1996, Cancer Res. 56:5238; Ichikawa et al., 1994, Cancer Res. 54:2299; Kuramochi et al., 1997, Prostate 31:14). These observations suggest that chromosome region 8p21-22 has an important role in the development of various tumors.
Efforts by others to identify tumor suppressor gene(s) located on chromosome 8p identified two candidate tumor suppressor genes, designated N33 and PRLTS (Bookstein et al., 1997, Br. J. Urol. 79(Suppl. 1):28; Bova et al., 1996, Genomics 35:46; MacGrogan et al., 1996, Genomics 35:55; Cher et al., 1994, Genes Chromosom. Cancer 11:153; Bookstein, et al., 1994, Genomics 24:317; Fujiwara et al., 1995, Oncogene 10:891; Komiya et al., 1997, Jpn. J. Cancer Res. 88:389). Gene N33 is located at position 8p22, near the MSR gene locus, but no point mutations in N33 have been associated with tumors. Four cancer-associated point mutations have been reported in PRLTS, which is located at position 8p21.3-22. The frequency of alterations in this gene was, however, very low. Thus, it is unlikely that either the N33 gene or the PRLTS gene are tumor suppressor genes associated with common cancers.
Until the present disclosure, the tumor suppressor gene(s) located at chromosome location 8p has not been identified. The failure of others to identify this gene has delayed development of diagnostic, therapeutic, and other useful methods and compositions which involve this tumor suppressor gene. The present invention enables these methods and compositions.